A small-molecule adipor agonist for type 2 diabetes and short life in obesity

ABSTRACT Adiponectin secreted from adipocytes binds to adiponectin receptors AdipoR1 and AdipoR2, and exerts antidiabetic effects via activation of AMPK and PPAR-α pathways, respectively.

Levels of adiponectin in plasma are reduced in obesity, which causes insulin resistance and type 2 diabetes. Thus, orally active small molecules that bind to and activate AdipoR1 and AdipoR2

could ameliorate obesity-related diseases such as type 2 diabetes. Here we report the identification of orally active synthetic small-molecule AdipoR agonists. One of these compounds,

AdipoR agonist (AdipoRon), bound to both AdipoR1 and AdipoR2 _in vitro_. AdipoRon showed very similar effects to adiponectin in muscle and liver, such as activation of AMPK and PPAR-α

pathways, and ameliorated insulin resistance and glucose intolerance in mice fed a high-fat diet, which was completely obliterated in AdipoR1 and AdipoR2 double-knockout mice. Moreover,

AdipoRon ameliorated diabetes of genetically obese rodent model _db/db_ mice, and prolonged the shortened lifespan of _db/db_ mice on a high-fat diet. Thus, orally active AdipoR agonists

such as AdipoRon are a promising therapeutic approach for the treatment of obesity-related diseases such as type 2 diabetes. Access through your institution Buy or subscribe This is a

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ACKNOWLEDGEMENTS We thank N. Kubota, K. Hara, I. Takamoto, Y. Hada, T. Kobori, H. Umematsu, S. Odawara, T. Aoyama, Y. Jing, S. Wei, K. Soeda and H. Waki for technical help and support; and

K. Miyata, Y. Nishibaba, M. Yuasa and A. Hayashi for technical assistance and support. This work was supported by a Grant-in-aid for Scientific Research (S) (20229008, 25221307) (to T.K.),

Grant-in-aid for Young Scientists (A) (23689048) (to M.I.), Targeted Proteins Research Program (to T.K.), the Global COE Research Program (to T.K.), Translational Systems Biology and

Medicine Initiative (to T.K.) and Translational Research Network Program (to M.O.-I.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan. Funding Program for

Next Generation World-Leading Researchers (NEXT Program) (to T.Y.) from Cabinet Office, Government of Japan. AUTHOR INFORMATION Author notes * Miki Okada-Iwabu, Toshimasa Yamauchi and Masato

Iwabu: These authors contributed equally to this work. AUTHORS AND AFFILIATIONS * Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo

113-0033, Japan Miki Okada-Iwabu, Toshimasa Yamauchi, Masato Iwabu, Ken-ichi Hamagami, Koichi Matsuda, Mamiko Yamaguchi, Kohjiro Ueki & Takashi Kadowaki * Department of Integrated

Molecular Science on Metabolic Diseases, 22nd Century Medical and Research Center, The University of Tokyo, Tokyo 113-0033, Japan Miki Okada-Iwabu, Toshimasa Yamauchi, Masato Iwabu & 

Takashi Kadowaki * Department of Molecular Medicinal Sciences on Metabolic Regulation, 22nd Century Medical and Research Center, The University of Tokyo, Tokyo 113-0033, Japan Miki

Okada-Iwabu, Toshimasa Yamauchi & Takashi Kadowaki * RIKEN Systems and Structural Biology Center, Tsurumi, Yokohama 230-0045, Japan, Teruki Honma, Hiroaki Tanabe, Tomomi Kimura-Someya, 

Mikako Shirouzu, Akiko Tanaka & Shigeyuki Yokoyama * Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba 305-8577, Japan Hitomi Ogata & Kumpei Tokuyama *

Open Innovation Center for Drug Discovery, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan, Tetsuo Nagano & Akiko Tanaka * Graduate School of Science, The

University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan, Shigeyuki Yokoyama Authors * Miki Okada-Iwabu View author publications You can also search for this author inPubMed Google Scholar *

Toshimasa Yamauchi View author publications You can also search for this author inPubMed Google Scholar * Masato Iwabu View author publications You can also search for this author inPubMed 

Google Scholar * Teruki Honma View author publications You can also search for this author inPubMed Google Scholar * Ken-ichi Hamagami View author publications You can also search for this

author inPubMed Google Scholar * Koichi Matsuda View author publications You can also search for this author inPubMed Google Scholar * Mamiko Yamaguchi View author publications You can also

search for this author inPubMed Google Scholar * Hiroaki Tanabe View author publications You can also search for this author inPubMed Google Scholar * Tomomi Kimura-Someya View author

publications You can also search for this author inPubMed Google Scholar * Mikako Shirouzu View author publications You can also search for this author inPubMed Google Scholar * Hitomi Ogata

View author publications You can also search for this author inPubMed Google Scholar * Kumpei Tokuyama View author publications You can also search for this author inPubMed Google Scholar *

Kohjiro Ueki View author publications You can also search for this author inPubMed Google Scholar * Tetsuo Nagano View author publications You can also search for this author inPubMed 

Google Scholar * Akiko Tanaka View author publications You can also search for this author inPubMed Google Scholar * Shigeyuki Yokoyama View author publications You can also search for this

author inPubMed Google Scholar * Takashi Kadowaki View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS M.O.-I., M.I., T.Y., T.H., K.-i.-H.,

K.M., M.Y., H.T., T.K-S., M.S., H.O., K.T. and A.T. performed experiments. T.K., T.Y., M.O.-I. and M.I. conceived the study. T.K., A.T., T.Y. and S.Y. supervised the study. T.Y., T.K.,

M.O.-I. and M.I. wrote the paper. All authors interpreted data. CORRESPONDING AUTHORS Correspondence to Toshimasa Yamauchi or Takashi Kadowaki. ETHICS DECLARATIONS COMPETING INTERESTS The

authors declare no competing financial interests. EXTENDED DATA FIGURES AND TABLES EXTENDED DATA FIGURE 1 PHOSPHORYLATION OF AMPK IN C2C12 MYOTUBES. Phosphorylation of AMPK normalized to the

amount of AMPK in C2C12 myotubes treated for 5 min with 15 µg ml−1 adiponectin or the indicated small-molecule compounds (10 μM). #, AdipoRon; ##, no. 112254; ###, no. 165073. EXTENDED DATA

FIGURE 2 DISTRIBUTION CURVES SHOWING _Z_ SCORES. A, Distribution curve showing _Z_ scores representing AMPK activity for all compounds tested in C2C12 myotubes shown in Extended Data Table

1 and Extended Data Fig. 1. The dashed line indicates the _Z_ score cut-off for compounds scored as hits, which showed higher activity than 80% of that seen with adiponectin. B, Distribution

curve showing _Z_ scores representing AdipoR dependency of AMPK activation for 39 compounds tested in C2C12 myotubes shown in Extended Data Table 2. Indicated are the location of AdipoRon,

another hit (no. 112254), and non-hit (no. 165073). EXTENDED DATA FIGURE 3 THE EFFECT OF ADIPORON ON COMPLEX I ACTIVITY, AND EXPRESSION OF _ADIPOR1_ AND _ADIPOR2_ MRNA IN C2C12 MYOTUBES

TRANSFECTED WITH THE INDICATED SIRNA DUPLEX. A, Complex I activities were measured with the indicated concentrations of rotenone or AdipoRon. B, C, _Adipor1_ (B) and _Adipor2_ (C) mRNA

levels were analysed by RT–qPCR. All values are presented as mean ± s.e.m. A, _n_ = 3–7; B, C, _n_ = 3 each; *_P_ < 0.05 and **_P_ < 0.01 compared to control or unrelated siRNA cells.

NS, not significant. EXTENDED DATA FIGURE 4 ADIPORON BINDING TO ADIPOR1 AND ADIPOR2. A–D, Binding and Scatchard analyses of [3H]AdipoRon to primary hepatocytes from wild-type (A),

_Adipor2_−/− knockout (B), _Adipor1_−/− knockout (C) and _Adipor1_−/− _Adipor2_−/− double-knockout (D) mice. E–H, Concentration-dependent competitive [3H]AdipoRon binding to primary

hepatocytes from wild-type (E), _Adipor2_−/− knockout (F), _Adipor1_−/− knockout (G) and _Adipor1_−/− _Adipor2_−/− double-knockout (H) mice. Binding analyses were performed using the

indicated concentrations of AdipoRon. c.p.m., counts per minute. EXTENDED DATA FIGURE 5 RAW DATA OF FIG. 2 AND TIME COURSE OF GLUCOSE-LOWERING EFFECT OF ADIPORON. A–M, Raw data of Fig. 2a

(A), Fig. 2d, left (B, C), Fig. 2d, right (D, E), Fig. 2e, left (F, G), Fig. 2e, right (H, I), Fig. 2g, left (J, K) and Fig. 2g, right (L, M). N, Time course of glucose-lowering effect of

AdipoRon. Data are calculated from data in Fig. 4a. The glucose-lowering effect of AdipoRon was obtained by the following equation and expressed as %: (vehicle plasma glucose − AdipoRon

plasma glucose)/vehicle plasma glucose. All values are presented as mean ± s.e.m. EXTENDED DATA FIGURE 6 THE EFFECTS OF COMPOUNDS 112254 AND 165073 ON INSULIN RESISTANCE AND GLUCOSE

INTOLERANCE VIA ADIPOR. A, B, Chemical structures of compounds 112254 (A) and 165073 (B). C–J, Plasma glucose (C left, D left, F, G left, H left, J), plasma insulin (C right, D right, G

right, H right) and insulin resistance index (E, I) during oral glucose tolerance test (OGTT) (1.0 g glucose per kg body weight) (C, D, G, H) or during insulin tolerance test (ITT) (0.5 U

insulin per kg body weight) (F, J), in wild-type and _Adipor1_−/− _Adipor2_−/− double-knockout mice, treated with or without compounds 112254 or 165073 (50 mg per kg body weight). All values

are presented as mean ± s.e.m. C–F, _n_ = 10 each; G–J, _n_ = 7 each from 2, 3 independent experiments, *_P_ < 0.05 and **_P_ < 0.01 compared to control or as indicated. NS, not

significant. EXTENDED DATA FIGURE 7 THE EFFECTS OF ADIPORON ON GLUCOSE METABOLISM IN _ADIPOR1_−/−, _ADIPOR2_−/− AND _ADIPOR1_−/− _ADIPOR2_−/− MICE. A, Triglyceride content (A) and TBARS (B)

in skeletal muscle from wild-type or _Adipor1_−/− _Adipor2_−/− double-knockout mice treated with or without AdipoRon (50 mg per kg body weight). C–G, The effects of AdipoRon on glucose

metabolism in _Adipor1_−/−, _Adipor2_−/− and _Adipor1_−/− _Adipor2_−/− mice. Plasma glucose (C–F, left panels), plasma insulin (C–F, right panels) and insulin resistance index (G) during

oral glucose tolerance test (OGTT) (1.0 g glucose per kg body weight). All values are presented as mean ± s.e.m. A–D, F, _n_ = 10 each; E, _n_ = 7 each; G, _n_ = 7–10; *_P_ < 0.05 and

**_P_ < 0.01 compared to vehicle mice. NS, not significant. EXTENDED DATA FIGURE 8 CHEMICAL STRUCTURES AND ADIPOR DEPENDENCY OF AMPK ACTIVATION. A–D, Chemical structures of AdipoRon (A),

compound 168198 (B), compound 112254 (C) and compound 103694 (D). Within the 1-benzyl 4-substituted 6-membered cyclic amine moiety, the cyclic amine moiety is surrounded by a dashed red

circle, and the aromatic ring is surrounded by a light green circle. Cyan and dark green circles surround the carbonyl group and the terminal aromatic ring, respectively, located on the

opposite side from the benzyl cyclic amine. E, Phosphorylation and amount of AMPK in C2C12 myotubes treated for 5 min with the indicated small-molecule compounds. Phosphorylation and amount

of AMPK in C2C12 myotubes, treated for 5 min with the indicated small-molecule compounds (10 μM) (% relative to adiponectin). F, AdipoR dependency of AMPK activation. Phosphorylation and

amount of AMPK in C2C12 myotubes and transfected with or without the AdipoR1 siRNA duplex, treated for 5 min with the indicated small molecule. AdipoR-dependency ratios were obtained by the

following equation: 100 − (ratio for those transfected with the AdipoR1 siRNA duplex/ratio for those transfected without the AdipoR1 siRNA duplex) × 100 (%). SUPPLEMENTARY INFORMATION

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THIS ARTICLE Okada-Iwabu, M., Yamauchi, T., Iwabu, M. _et al._ A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity. _Nature_ 503, 493–499 (2013).

https://doi.org/10.1038/nature12656 Download citation * Received: 06 June 2012 * Accepted: 10 September 2013 * Published: 30 October 2013 * Issue Date: 28 November 2013 * DOI:

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